1. Field of the Invention
The present invention relates generally to biochemical sensors used to measure the concentration of a specific chemical dissolved within a fluid, and more particularly, to a biochemical sensor formed by thin film microelectronic fabrication techniques in order to provide a thermopile used to generate a voltage signal representative of the concentration of a chemical dissolved within a fluid.
2. Description of the Prior Art
There has been a well recognized need in the medical field for a sensor capable of being implanted in a human body for providing a continuous indication of the concentration of glucose in the bloodstream. Implantable drug dispensers have been developed to dispense insulin into the bloodstream of persons having diabetes in order to simulate the manner in which the pancreas functions in a non-diabetic. Widespread application of such insulin dispensing devices has largely been frustrated due to the unavailability of an implantable sensor capable of monitoring glucose levels for controlling the rate at which the insulin is dispensed into the bloodstream. Publications stressing the need for the development of such an implantable glucose sensor include Albisser and Spencer, "Electronics and the Diabetic," IEEE Transactions on Biomedical Engineering, Vol. BME-29, No. 4, April 1982; Wall Street Journal, "Medtronic Researchers Try Hard to Develop In-Body Drug Device", Apr. 12, 1983 and Diabetes Care, Vol. 5, No. 3, May-June 1982, "Symposium on Potentially Implantable Glucose Sensors". While the need for an implantable sensor of the type capable of measuring glucose levels has perhaps received the most attention, there are many other drugs besides insulin which might be beneficially dispensed with an automatic dispenser and which require sensors responsive to chemicals other than glucose in order to control the rate at which such drugs are dispensed. There is also a need to continuously measure the concentration of many chemicals in the body independent of their control.
Various types of enzyme probes are known in the art for the purpose of measuring the concentration of glucose or other chemicals dissolved within a solution. For example, Guilbault has recently reviewed a large number of articles describing this type of probe; see Guilbault, G. C., "Future of Biomembrane Probes," Theory, Design and Biomedical Applications of Solid State Chemical Sensors, pp. 193-204, CRC Press, 1978. Enzyme probes of this type have been used to measure glucose. In "Problems in Adapting a Glucose-Oxidase Electrochemical Sensor into an Implantable Glucose-Sensing Device," Diabetes Care, Vol. 5, No. 3, May-June 1982, the author describes a type of glucose electrode wherein the enzyme glucose oxidase is immobilized upon a polarographic electrode in order to chemically react glucose which contacts the electrode. A polarographic electrode is typically made from a noble metal wire and is biased with an electrical voltage for causing an electrochemical reduction reaction. The enzyme glucose oxidase facilitates the oxidation of glucose into gluconic acid and hydrogen peroxide and consumes oxygen in the process. The disappearance of oxygen, or the appearance of hydrogen peroxide, is measured using a standard polarographic electrode and is proportional to the amount of glucose consumed. Such a glucose electrode has not been successfully implanted for long periods because polarographic measurements are very unstable.
An alternate method of measuring glucose concentrations is to measure the heat evolved by the glucose oxidase enzymatic reaction, as described in U.S. Pat. No. 3,878,049, issued to Tannenbaum, et al. This patent discloses a biochemical temperature sensing analyzer including an uncoated reference thermistor and a second thermistor coated with an enzyme, such as glucose oxidase. The patent specification states that the temperature sensing elements may be thermistors, thermocouples, or pyroelectric devices for generating an electrical signal proportional to the difference in temperature between the enzyme-coated and non-enzyme coated temperature sensing elements. However, the disclosed apparatus includes a mechanism for continuously stirring the reactant-containing liquid, as well as a constant temperature bath into which a container housing the reactant-containing liquid is immersed. Although Tannenbaum refers to this device as a thermal enzyme probe, it is not a "probe" in the classical sense, but rather a benchtop chemical analyzer. Given such limitations, it is clear that such an apparatus is not suitable for being implanted within a human body.
U.S. Pat. No. 3,972,681, issued to Clack et al., discloses a flow-through type thermal detector including a pair of parallel fluid flow paths; one of these paths includes a reactor column wherein an enzyme is immobilized on the surface of small glass beads packed in the column. Similarly, U.S. Pat. No. 4,021,307, issued to Mosbach, discloses a heat sensor disposed within a flow path wherein an enzyme is immobilized within a packed column of glass beads. For obvious reasons, such flow-through systems do not lend themselves to the production of an implantable thermal enzyme electrode.
The patents mentioned above typically suggest the usage of one or more thermistors with a benchtop apparatus for sensing the temperature change caused by a chemical reaction. The practical application of such apparatus has been hampered because they employ thermistors; since thermistors are resistive devices, temperature sensing is performed by conducting a current therethrough and measuring the voltage thereacross. However, the passage of current through the thermistor dissipates power therein and gives rise to self-heating within the thermistor; such self-heating adds an offset to the temperature differential induced solely by the chemical reaction of the glucose or other dissoved chemical. Further, any fluid flow or movement of the thermistor within the fluid will result in a change of the temperature of the thermistor due to variable amounts of heat dissipation. Moreover, the application of current and/or voltage to such thermistors may be regarded as undesirable, particularly for a sensor which is to be implanted within a human body; excitation voltages establish electric fields which are believed to attract proteins and which may activate blood clotting. Finally, thermistors are difficult to match and are subject to drifting whereby two thermistors which may be matched to one another at a given ambient temperature nonetheless become mismatched at a different ambient temperature, thus giving rise to the need for constant temperature baths and/or preheating mechanisms within the abovementioned prior art sensors. Some of these problems have been discussed in a recent paper by Fulton, Cooney and Weaver, "Thermal Enzyme Probe with Differential Temperature Measurements in a Laminar Flow-Through Cell", Analytical Chemistry, Vol. 52, No. 3, March 1980, pp. 505-508.
Yet another problem which has been encountered with prior art thermal enzyme probes of the type which employ both enzyme coated and non-enzyme coated probes is that, even in a well stirred solution, thermal eddies exist which can give rise to an apparent temperature differential between the enzyme-coated and non-enzyme coated probes irrespective of the concentration of the chemical under test. Such thermal eddies may thereby give rise to false indications of concentrations of the chemical under test, or alternatively, may tend to offset temperature differentials which would otherwise be present due to the chemical reaction of the chemical under test.
It has also been suggested that thin film thermopiles may be used to measure temperature differentials for certain biomedical applications. In Wunderman and Muray, Temperature, Its Measurement and Control in Science and Industry, Vol. 4, Part 3, page 2151, published by The Instrument Society of America, Pittsburgh, Pa. 1972, the construction and application of thin film thermopiles is described for directly measuring temperature differentials on the skin of a segment of the body and for use as detectors in microcalorimetry. Thin film thermopiles are also discussed in G. R. Lahiji, A Monolithic Thermopile Detector Fabricated Using Integrated Circuit Technology, Ph.D. Dissertation, Department of Electrical and Computer Engineering, Stanford University, June 1981. However, neither of the aforementioned papers discloses or suggests the use of such a thin film thermopile in conjunction with an immobilized substance, such as an enzyme or other catalyst coating, for the purpose of sensing the concentration of a chemical within a solution.
Accordingly, it is an object of the present invention to provide a chemical transducer for biomedical applications and capable of being implanted within the human body for sensing chemical concentrations in body fluids.
It is another object of the present invention to provide such a chemical transducer adapted to detect concentrations of glucose in the bloodstream by measuring the heat of reaction associated with the enzymatic chemical decomposition of glucose using glucose-specific enzymes.
It is another object of the present invention to provide such a chemical transducer wherein living plant or bacteria cells, or parts thereof, are used to metabolize a chemical under test, and wherein the transducer measures the heat of metabolism associated therewith.
It is still another object of the present invention to provide such a chemical transducer which is highly sensitive while being relatively compact and disposable.
It is yet another object of the present invention to provide such a chemical transducer which is relatively convenient and inexpensive to manufacture and which may be fabricated using conventional integrated circuit thin-film metal deposition and microlithography techniques.
A further object of the present invention is to provide such a chemical transducer or sensor which avoids the requirements for the application of excitation voltages and/or currents in order to obtain a measurement of the concentration of the chemical under test, and which thereby avoids self-heating within the sensor.
A still further object of the present invention is to provide such a sensor capable of sensing a temperature differential within a solution under test and exhibiting high common mode rejection with respect to background ambient temperatures of the solution, thereby avoiding drifting/mismatch problems encountered with differential thermistor sensing, and avoiding the need for constant temperature water baths.
Another object of the present invention is to provide such a sensor adapted to differentially sense temperature between two physical points within the fluid under test and wherein the distance between such two physical points is kept to a minimum to negate the effects of thermal eddies within the fluid under test.
Still another object of the present invention is to provide such a sensor which may be used as an inexpensive and disposable in-vitro clinical analyzer for measuring concentrations of a chemical dissolved in a fluid within a clinical laboratory while avoiding the need for controlled water baths, pre-heating mechanisms, and/or specialized flow paths for the solution under test.
These and other objects of the present invention will become more apparent to those skilled in the art as the description thereof proceeds.